P692: Identification of an intronic Alu insertion in the SYNE1 gene associated with autosomal recessive spinocerebellar ataxia type 8

The spectrin repeat-containing nuclear envelope protein 1 (SYNE1) gene encodes a multi-isomeric protein called Nesprin-1, important for maintaining the structure and function of the cerebellum. Mutations in this gene are thus commonly associated with slowly progressive cerebellar syndromes with an adult onset, including autosomal recessive spinocerebellar ataxia 1 and 8 (SCAR1/SCAR8). Herein, we report the case of an adult patient referred to the New Brunswick genetics clinic for evaluation of late onset of balance and fine motor difficulties, as well as cerebellar degeneration with dysarthria. A 41-year-old female patient first noticed balance issues and clumsiness after giving birth and, five years later, developed progressive dysarthria and fine motor dysfunction, with worsening of her balance and a few falls sustained. The patient’s gait was narrow and unstable, drifting to the left, with difficulties walking on tip toes and heels. Brain MRI showed isolated cerebellar atrophy affecting the vermis, and brain SPECT/CT was only relevant for significant abnormality in the cerebellum. Additional testing included a microarray for chromosomal anomalies, blood gas, lactate, and ammonia, which were all normal. Plasma amino acids, urine organic acids, very long chain fatty acids, sterol profile, and screen for congenital defects of glycosylation revealed no significant findings. With this initial workup being non-conclusive, a targeted exome to the patient’s phenotype was performed. A targeted exome sequencing revealed the patient to be heterozygous for SYNE1 c.1371+2del, a likely pathogenic variant, and SYNE1 c. 9168-32_9168-33insAlu, which was initially classified as a variant of uncertain significance because a retrotransposable insertion in SYNE1 at any position has never been associated with disease, nor was it reported in disease-related variation databases. To better understand the functional impact of c. 9168-32_9168-33insAlu, a SYNE1-specific RNA sequencing targeted analysis was completed. Primary findings revealed a positive result with aberrant splicing located at the region of the c. 9168-32_9168-33insAlu variant. Specifically, half of the sequenced transcript showed an aberrant splice junction extending from the splice donor site of exon 57 to the splice acceptor site of exon 59 of SYNE1, consistent with skipping exon 58 on one allele. In light of these results and investigations, the SYNE1 c. 9168-32_9168-33insAlu variant was shown to cause a frameshift mutation, resulting in premature termination and a loss of normal protein function. This led to its reclassification as likely pathogenic and allowed the medical team to confidently make a diagnosis of SCAR8 in this patient.

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